The present invention relates to cyclic amino compounds or pharmacologically acceptable salts thereof each having excellent platelet aggregation inhibitory action and inhibitory action against the advance of arteriosclerosis, to compositions for the prevention or treatment of embolism, thrombosis or arteriosclerosis each of which comprises any one of said compounds, to use of said compounds for the preparation of a medicament for the prevention or treatment of embolism, thrombosis or arteriosclerosis, to a method for the prevention or treatment of embolism, thrombosis or arteriosclerosis, which comprises administering a pharmacologically effective amount of any one of said compounds to warm-blooded animals, and to a process for the preparation of said compounds.
As cyclic amino compounds having platelet aggregation inhibitory action, known are, for example, hydropyridine derivatives [ex. U.S. Pat. No. 4,051,141, Japanese Patent Application Kokai No. Sho 59-27895 (EP 99802), Japanese Patent Application Kokai No. Hei 6-41139 (EP 542411), WO 98/08811, etc.].
As a result of investigation on the pharmacological action of cyclic amino compounds for many years, the present inventors have found that specific cyclic amino compounds have excellent platelet aggregation inhibitory action and inhibitory action against the advance of arteriosclerosis (particularly, the platelet aggregation inhibitory action) and is useful as a preventive agent or remedy (particularly, as a remedy) for embolism, thrombosis and arteriosclerosis (particularly, embolism or thrombosis), leading to the completion of the present invention.
The present invention provides cyclic amino compounds or pharmacologically acceptable salts thereof having excellent platelet aggregation inhibitory action and inhibitory action against the advance of arteriosclerosis, compositions for the prevention or treatment of embolism, thrombosis or arteriosclerosis each of which comprises any one of said compounds, use of said compounds for the preparation of a medicament for the prevention or treatment of embolism, thrombosis or arteriosclerosis, a method for the prevention or treatment of embolism, thrombosis or arteriosclerosis, which comprises administering a pharmacologically effective amount of any one of said compounds to warm-blooded animals, and a process for the preparation of said compounds.
The cyclic amino compounds according to the present invention have the following formula: 
In the above-described formula,
R1 represents a substituted or unsubstituted phenyl group (the substituted of said group being a halogen atom, a C1-C4 alkyl group, a fluoro-substituted-(C1-C4 alkyl) group, a C1-C4 alkoxy group, a fluoro-substituted-(C1-C4 alkoxy) group, a cyano group or a nitro group);
R2 represents a substituted or unsubstituted C1-C8 aliphatic acyl group (the substituent of said group being a halogen atom, a C1-C4 alkoxy group or a cyano group), a substituted or unsubstituted benzoyl group (the substituent of said group being a halogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group), or a (C1-C4 alkoxy)carbonyl group; and
R3 represents a substituted, 3- to 7-membered, saturated cyclic amino group which may optionally have a fused ring {said cyclic amino group is substituted with a group having the formula of xe2x80x94Sxe2x80x94Xxe2x80x94R4 [wherein, R4 represents a substituted or unsubstituted phenyl group (the substituent of said group being a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a nitro group or a cyano group), a substituted or unsubstituted C1-C6 alkyl group [the substituent of said group being an amino group, a hydroxyl group, a carboxyl group, a (C1-C4 alkoxy)carbonyl group, a group having the formula of xe2x80x94NHxe2x80x94A1 (wherein, A1 represents an xcex1-amino acid residue) or group having the formula of xe2x80x94COxe2x80x94A2 (wherein, A2 represents an xcex1-amino acid residue)], or a C3-C8 cycloalkyl group, and X represents a sulfur atom, a sulfinyl group or a sulfonyl group], and said cyclic amino group may optionally be further substituted with a group having the formula of xe2x95x90CR5R6 [wherein, R5 and R6 are the same or different and each independently represents a hydrogen atom, a C1-C4 alkyl group, a carboxyl group, a (C1-C4 alkoxy)carbonyl group, a carbamoyl group, a (C1-C4 alkyl)carbamoyl group or a di-(C1-C4 alkyl)carbamoyl group]}.
In the above-described definition of R1, examples of the xe2x80x9chalogen atomxe2x80x9d serving as a substituent for the substituted phenyl group include fluorine, chlorine, bromine and iodine atoms, of which the fluorine, chlorine and bromine atoms are preferred, and the fluorine and chlorine atoms are particularly preferred.
In the definition of R1, examples of the xe2x80x9cC1-C4 alkyl groupxe2x80x9d serving as a substituent for the substituted phenyl group include straight or branched C1-C4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and t-butyl groups, of which the methyl and ethyl groups are preferred, and the methyl group is most preferred.
In the definition of R1, examples of the xe2x80x9cfluoro-substituted-(C1-C4 alkyl) groupxe2x80x9d serving as a substituent for the substituted phenyl group include straight or branched fluoro-substituted-(C1-C4 alkyl) groups such as fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2-fluorobutyl, 3-fluorobutyl and 4-fluorobutyl groups, of which the difluoromethyl and trifluoromethyl groups are preferred, and the trifluoromethyl group is most preferred.
In the definition of R1, examples of the xe2x80x9cC1-C4 alkoxy groupxe2x80x9d serving as a substituent for the substituted phenyl group include straight or branched C1-C4 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy and t-butoxy groups, of which the methoxy and ethoxy groups are preferred, and the methoxy group is most preferred.
In the definition of R1, examples of the xe2x80x9cfluoro-substituted-C1-C4 alkoxy) groupxe2x80x9d serving as a substituent for the substituted phenyl group include straight or branched fluoro-substituted-(C1-C4 alkoxy) groups such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-fluoropropoxy, 3-fluoropropoxy, 2-fluoroisopropoxy and 4-fluorobutoxy groups, of which the difluoromethoxy and trifluoromethoxy groups are preferred, and the trifluoromethoxy group is most preferred.
In the definition of R1, preferred examples of the substituent for the substituted phenyl group include the halogen atoms, methyl group, ethyl group, difluoromethyl group, trifluoromethyl group, methoxy group, ethoxy group, difluoromethoxy group, trifluoromethoxy group, cyano group and nitro group, or which the fluorine atom, chlorine atom, bromine atom, trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group and nitro group are more preferred, and the fluorine and chlorine atoms are particularly preferred. The number of substituents preferably ranges from 1 to 3, of which 1 or 2 are more preferred, and 1 is most preferred. The position of the substituent is preferably the 2- or 4-position, of which the 2-position is most preferred.
In the definition of R2, examples of the xe2x80x9caliphatic acylxe2x80x9d part of the substituted or unsubstituted C1-C8 aliphatic acyl group include straight or branched C1-C8 alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl and octanoyl groups, and (C3-C7 cycloalkyl)carbonyl groups such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and cycloheptylcarbonyl groups, of which C2-C4 alkanoyl groups and (C3-C6 cycloalkyl)carbonyl groups are preferred; the acetyl, propionyl, isobutyryl, cyclopropylcarbonyl and cyclobutylcarbonyl groups are more preferred; the propionyl and cyclopropylcarbonyl groups are still more preferred; and the cyclopropylcarbonyl group is most preferred.
The xe2x80x9chalogen atomxe2x80x9d and xe2x80x9cC1-C4 alkoxy groupxe2x80x9d serving as a substituent for the aliphatic acyl group have the same meaning as that defined as the substituent for the xe2x80x9csubstituted phenyl groupxe2x80x9d in the definition of R1. Preferred examples of the substituent for the aliphatic acyl group include a fluorine atom, chlorine atom, methoxy group, ethoxy group and cyano group, of which the fluorine and chlorine atoms are more preferred, and the fluorine atom is most preferred. The number of substituents preferably ranges from 1 to 3, of which 1 and 2 are more preferred, and 1 is most preferred.
Specific examples of the xe2x80x9csubstituted aliphatic acyl groupxe2x80x9d include fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, trichloroacetyl, bromoacetyl, iodoacetyl, 3-fluoropropionyl, 3-chloropropionyl, 3-bromopropionyl, 3-iodopropionyl, 4-fluorobutyryl, 4-chlorobutyryl, 5-fluorovaleryl, methoxyacetyl, 3-methoxypropionyl, 4-methoxybutyryl, 5-methoxyvaleryl, ethoxyacetyl, 3-ethoxypropionyl, 4-ethoxybutyryl, 5-ethoxyvaleryl, cyanoacetyl, 3-cyanopropionyl, 4-cyanobutyryl, 5-cyanovaleryl, 2-fluorocyclopropylcarbonyl, 2,2-difluorocyclopropylcarbonyl, 2-chlorocyclopropylcarbonyl, 2-bromocyclopropylcarbonyl, 2-fluorocyclobutylcarbonyl, 2-chlorocyclobutylcarbonyl, 2-fluorocyclopentylcarbonyl, 2-chlorocyclopentylcarbonyl, 2-fluorocyclohexylcarbonyl, 2-chlorocyclohexylcarbonyl, 2-methoxycyclopropylcarbonyl, 2-methoxycyclobutylcarbonyl, 2-methoxycyclopentylcarbonyl, 2-methoxycyclohexylcarbonyl, 2-ethoxycyclopropylcarbonyl, 2-ethoxycyclobutylcarbonyl, 2-ethoxycyclopentylcarbonyl, 2-ethoxycyclohexylcarbonyl, 2-cyanocyclopropylcarbonyl, 2-cyanocyclobutylcarbonyl, 2-cyanocyclopentylcarbonyl and 2-cyanocyclohexylcarbonyl groups,
of which the fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, 3-fluoropropionyl, 3-chloropropionyl, methoxyacetyl, 3-methoxypropionyl, ethoxyacetyl, cyanoacetyl, 3-cyanopropionyl, 2-fluorocyclopropylcarbonyl, 2,2-difluorocyclopropylcarbonyl, 2-chlorocyclopropylcarbonyl, 2-fluorocyclobutylcarbonyl, 2-chlorocyclobutylcarbonyl, 2-fluorocyclopentylcarbonyl, 2-fluorocyclohexylcarbonyl, 2-methoxycyclopropylcarbonyl, 2-ethoxycyclopropylcarbonyl and 2-cyanocyclopropylcarbonyl groups are preferred,
The fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, 3-fluoropropionyl, 2-fluorocyclopropylcarbonyl, 2-chlorocyclopropylcarbonyl and 2-fluorocyclobutylcarbonyl groups are more preferred, and
the fluoroacetyl, difluoroacetyl, trifluoroacetyl, 3-fluoropropionyl and 2-fluorocyclopropylcarbonyl groups are particularly preferred.
The xe2x80x9chalogen atomxe2x80x9d, xe2x80x9cC1-C4 alkyl groupxe2x80x9d and xe2x80x9cC1-C4 alkoxy groupxe2x80x9d serving as a substituent for the substituted benzoyl group in the definition of R2 have the same meaning as that defined as the substituent for the xe2x80x9csubstituted phenyl groupxe2x80x9d in the above-described definition of R1. Preferred examples include the fluorine atom, chlorine atom, methyl group, ethyl group, methoxy group and ethoxy group, of which the fluorine atom and chlorine atom are more preferred and the fluorine atom is most preferred. The number of substituents preferably ranges from 1 to 3, of which 1 and 2 are more preferred and 1 is most preferred.
Examples of the xe2x80x9c(C1-C4 alkoxy)carbonyl groupxe2x80x9d in the definition of R2 include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl and t-butoxycarbonyl groups, of which the methoxycarbonyl and ethoxycarbonyl groups are preferred and the methoxycarbonyl group is most preferred.
In the definition of R3, the part of the xe2x80x9csaturated cyclic amino group group which may optionally have a fused ringxe2x80x9d of the xe2x80x9csubstituted, 3- to 7-membered, saturated cyclic amino group which may optionally have a fused ringxe2x80x9d is a saturated cyclic amino group having in total from 2 to 8 carbon atoms in one or more rings, and which may optionally have a fused ring and may have an additional oxygen, nitrogen or sulfur atom, such as 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 2H-hexahydroazepin-1-yl, 7-azabicyclo[3.1.1]-heptan-7-yl, 8 -azabicyclo[3.2.1]octan-8-yl, 9-azabicyclo[3.3.1]nonan-9-yl, 4-morpholinyl, 4-thiomorpholinyl and 4-piperazinyl groups, of which the 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 7-azabicyclo[3.1.1]heptan-7-yl, 8-azabicyclo-[3.2.1]octan-8-yl, 9-azabicyclo-[3.3.1]nonan-9-yl, 4-morpholinyl and 4-thiomorpholinyl groups are preferred; the 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 8-azabicyclo[3.2.1]octan-8-yl and 9 -azabicyclo[3.3.1]nonan-9-yl groups are more preferred; the 1-acetidinyl, 1-pyrrolidinyl, 1-piperidinyl and 8-azabicyclo[3.2.1]octan-8-yl groups are still more preferred; and the 1-azetidinyl, 1-pyrrolidinyl and 1-piperidinyl groups are particularly preferred. The group is attached, via a nitrogen atom of the ring thereof, to the adjacent carbon atom (the carbon atom to which R1 and R2 are attached).
Preferred examples of the xe2x80x9csubstituted 3- to 7-membered, saturated cyclic amino group which may be cyclocondensedxe2x80x9d in the definition of R3 include 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-azetidinyl, 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-pyrrolidinyl, 3- or 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-piperidinyl, 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-3-(xe2x95x90CR5R6)-1-piperidinyl and 8-aza-3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-bicyclo[3.2.1]octan-8-yl groups, of which 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-azetidinyl, 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-pyrrolidinyl, 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-piperidinyl and 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-3-(xe2x95x90CR5R6)-1-piperidinyl groups are most preferred.
The xe2x80x9chalogen atomxe2x80x9d, xe2x80x9cC1-C4 alkyl groupxe2x80x9d and xe2x80x9cC1-C4 alkoxy groupxe2x80x9d serving as a substituent for the xe2x80x9csubstituted phenyl groupxe2x80x9d in the definition of R4 have the same meaning as that defined in the above-described definition of R1. Preferred examples of the substituent for the substituted phenyl group in R4 include halogen atoms and methyl, ethyl, methoxy, ethoxy, nitro and cyano groups, of which the fluorine atom, chlorine atom, bromine atom, methyl group, methoxy group, nitro group and cyano group are more preferred, and the fluorine atom, chlorine atom, methyl group, methoxy group and nitro group are particularly preferred. The number of substituents preferably ranges from 1 to 3, or which 1 or 2 is more preferred, and 1 is most preferred.
The part of the xe2x80x9cC1-C6 alkyl groupxe2x80x9d of the xe2x80x9csubstituted or unsubstituted C1-C6 alkyl groupxe2x80x9d in the definition of R4 includes C1-C4 alkyl groups having the same meaning as defined above as the substituent for the xe2x80x9csubstituted phenyl groupxe2x80x9d in R1, or pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl groups, of which the straight C1-C6 alkyl group such as methyl, ethyl, propyl, butyl, pentyl or hexyl is preferred, the straight C1-C4 alkyl group such as methyl, ethyl, propyl or butyl is more preferred, and the methyl, ethyl or propyl group is particularly preferred.
The xe2x80x9c(C1-C4 alkoxy)carbonyl groupxe2x80x9d serving as a substituent for the xe2x80x9csubstituted C1-C6 alkyl groupxe2x80x9d in the definition of R4 has the same meaning as that defined above in R2 and the methoxycarbonyl or ethoxycarbonyl group is preferred.
Examples of the xe2x80x9cxcex1-amino acid residuexe2x80x9d of A1 in the group having the formula of xe2x80x94NHxe2x80x94A1 which serves as a substituent for the xe2x80x9csubstituted C1-C6 alkyl groupxe2x80x9d in the definition of R4 include amino acid residues each having a partial structure obtained by removing a hydroxy group from the carboxyl group of an xcex1-amino acid, such as glycyl, alanyl, valinyl, leucinyl, phenylglycyl, phenylalanyl, xcex1-aspartyl, xcex2-aspartyl, xcex1-glutamyl and xcex3-glutamyl groups, of which the glycyl, alanyl, xcex2-aspartyl and xcex3-glutamyl groups are preferred, the glycyl and xcex3-glutamyl groups are more preferred, and the xcex3-glutamyl group is most preferred.
Examples of the xe2x80x9cxcex1-amino acid residuexe2x80x9d of A2 in the group having the formula of xe2x80x94COxe2x80x94A2 which serves as a substituent for the xe2x80x9csubstituted C1-C6 alkyl groupxe2x80x9d in the definition of R4 include amino acid residues each having a partial structure obtained by removing a hydrogen atom from the amino group of an xcex1-amino acid, such as glycino, alanino, valino, leucino, phenylglycino, phenylalanino, asparto and glutamo groups, of which the glycino, alanino, valino, leucino, phenylglycino and phenylalanino groups are preferred, the glycino, alanino and valino groups are more preferred, and the glycino group is most preferred.
Preferred examples of the substituent for the xe2x80x9csubstituted C1-C6 alkyl groupxe2x80x9d in R4 include an amino group, a hydroxy group, a carboxyl group, (C1-C4 alkoxy)carbonyl groups, groups having the formula xe2x80x94NHxe2x80x94A1a (wherein, A1a represents a glycyl, alanyl, xcex2-aspartyl or xcex3-glutamyl group) and groups having the formula xe2x80x94COxe2x80x94A2a (wherein, A2a represents a glycino, alanino, valino, leucino, phenylglycino or phenylalanino group), or which more preferred are:
the amino group, hydroxy group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, groups having the formula xe2x80x94NHxe2x80x94A1b (wherein, A1b represents a glycyl or xcex3-glutamyl group) and groups having the formula xe2x80x94COxe2x80x94A2b (wherein, A2b represents a glycino, alanino or valino group), of which the still more preferred groups are:
the amino group, hydroxyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, groups having the formula xe2x80x94NHxe2x80x94A1c (wherein, A1c represents a xcex3-glutamyl group) and groups having the formula of xe2x80x94COxe2x80x94A2c (wherein, A2c represents a glycino group), and the particularly preferred groups are:
the amino group, hydroxy group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, groups having the formula: xe2x80x94NHxe2x80x94A1c (wherein, A1c has the same meaning as described above) and groups having the formula of xe2x80x94COxe2x80x94A2c (wherein, A2c has the same meaning as described above)
The number of substituents for the xe2x80x9csubstituted C1-C6 alkyl groupxe2x80x9d in the definition of R4 is preferably 1 or 2. When the number of substituents is 2, the amino group, hydroxyl group or group having the formula of xe2x80x94NHxe2x80x94A1 attached to the same carbon atom as that to which the carboxyl group or group having the formula of xe2x80x94COxe2x80x94A2 is attached is particularly preferred.
Examples of the xe2x80x9cC3-C8 cycloalkyl groupxe2x80x9d in the definition of R4 include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups, of which the cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups are preferred, and the cyclopentyl and cyclohexyl groups are particularly preferred.
The xe2x80x9cC1-C4 alkyl groupxe2x80x9d in the definition of R5 and R6 has the same meaning as that defined in the above-described substituent of the xe2x80x9csubstituted phenyl groupxe2x80x9d in R1.
Examples of the xe2x80x9c(C1-C4 alkyl)carbamoyl groupxe2x80x9d in the definition of R5 and R6 include methylcarbonyl, ethoxycarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, s-butylcarbamoyl and t-butylcarbamoyl groups, of which the methylcarbamoyl and ethylcarbamoyl groups are preferred and the methylcarbamoyl group is most preferred.
Examples of the xe2x80x9cdi-(C1-C4 alkyl)carbamoyl groupxe2x80x9d in the definition of R5 and R6 may include N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-diisopropylcarbamoyl, N,N-dibutylcarbamoyl, N,N-diisobutylcarbamoyl, N,N-di-s-butylcarbamoyl and N,N-di-t-butylcarbamoyl groups, of which the N,N-dimethylcarbamoyl group and N,N-diethylcarbamoyl groups are preferred, and the N,N-dimethylcarbamoyl group is most preferred.
The xe2x80x9c(C1-C4 alkoxy)carbonyl groupxe2x80x9d in the definition of R5 and R6 has the same meaning as that defined in R2.
In the group having the formula of xe2x95x90CR5R6, it is preferred that R5 and R6 are the same or different and each independently represents a hydrogen atom, a methyl group, an ethyl group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group, an ethylcarbamoyl group, an N,N-dimethylcarbamoyl group or an N,N-diethylcarbamoyl group. It is more preferred that R5 represents the hydrogen atom, while R6 represents the hydrogen atom, methyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, methylcarbamoyl group or N,N-dimethylcarbamoyl group. It is particularly preferred that R5 represents the hydrogen atom, while R6 represents the carboxyl, methoxycarbonyl or ethoxycarbonyl group.
X preferably represents a sulfur atom or a sulfonyl group.
In the compounds (I) of the present invention, the carbon atom to which R1 is attached may be an asymmetric carbon atom. There therefore exist optical isomers based thereon. These isomers and mixtures thereof are also included in the compounds of the present invention. When, in the compound of formula (I), a double bond is contained in its molecule and/or a cycloalkyl group or a cyclic amino group contains two substituents, there exist cis/trans geometrical geometrical isomers based on them. These isomers and mixtures thereof are also embraced in the compounds of the present invention.
When the compounds (I) of the present invention contain as R5 or R6 a carboxyl group, they can be easily converted into their pharmacologically acceptable salts by treating it with a base. Examples of such salts include metal salts, for example, alkali metal salts such as sodium salts, potassium salts and lithium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, iron salts, zinc salts, copper salts, nickel salts and cobalt salts; and amine salts, for example, inorganic salts such as ammonium salts and organic salts such as t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,Nxe2x80x2-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts and tris(hydroxymethyl)aminomethane salts, of which the alkali metal salts (particularly, the sodium or potassium salts) are preferred.
The compounds (I) of the present invention can be converted into their pharmacologically acceptable salts easily by treating with an acid. Examples of such a salt include inorganic acid salts such as hydrochlorides, sulfates, nitrates and phosphates and organic acid salts such as acetates, propionates, butyrates, benzoates, oxalates, malonates, succinates, maleates, fumarates, tartrates, citrates, methanesulfonates, ethanesulfonates, benzenesulfonates and p-toluenesulfonates, of which the hydrochlorides, sulfates, nitrates, oxalates, succinates, fumarates and methanesulfonates are preferred.
In addition, the hydrates of each of the compounds (I) or their salts are also embraced in the present invention.
Out of the compounds of the present invention having the formula (I), the following ones are preferred:
(1) compounds wherein R1 represents a substituted phenyl group (the substituent being a halogen atom, methyl group, ethyl group, difluoromethyl group, trifluoromethyl group, methoxy group, ethoxy group, difluoromethoxy group, trifluoromethoxy group, cyano group or nitro group),
(2) compounds wherein R1 represents a substituted phenyl group (the substituent being a fluorine atom, chlorine atom, bromine atom, trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group or nitro group),
(3) compounds wherein R1 represents a substituted phenyl group (the substituent being a fluorine or chlorine atom),
(4) compounds wherein the number of substituents for the substituted phenyl group as R1 ranges from 1 to 3,
(5) compounds wherein the number of substituents for the substituted phenyl group as R1 is 1 or 2,
(6) compounds wherein the position of the substituent on the substituted phenyl group as R1 is the 2- or 4-position,
(7) compounds wherein R2 represents a substituted or unsubstituted C2-C4 alkanoyl or (C3-C6 cycloalkyl)carbonyl group (the substituent being a fluorine atom, chlorine atom, methoxy group, ethoxy group or cyano group), a substituted or unsubstituted benzoyl group (the substituent being a fluorine atom, chlorine atom, methyl group, ethyl group, methoxy group or ethoxy group), or a (C1-C4 alkoxy)carbonyl group,
(8) compounds wherein R2 represents a substituted or unsubstituted C2-C4 alkanoyl or (C3-C6 cycloalkyl)carbonyl group (the substituent being a fluorine or chlorine atom), a benzoyl group or a (C1-C4 alkoxy)carbonyl group,
(9) compounds wherein R2 represents a substituted or unsubstituted acetyl, propionyl, isobutyryl, cyclopropylcarbonyl, cyclobutylcarbonyl group (the substituent being a fluorine atom), methoxycarbonyl or ethoxycarbonyl group,
(10) compounds wherein R2 represents a propionyl, cyclopropylcarbonyl, methoxycarbonyl or ethoxycarbonyl group,
(11) compounds wherein R3 represents a 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-azetidinyl, 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-pyrrolidinyl, 3- or 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-piperidinyl, 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-3-(xe2x95x90CR5R6)-1-piperidinyl or 8-aza-3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-bicyclo[3.2.1]octan-8-yl group,
R4 represents a substituted or unsubstituted phenyl group (the substituent being a halogen atom, methyl group, ethyl group, methoxy group, ethoxy group, nitro group or cyano group), a substituted or unsubstituted straight C1-C6 alkyl group [the substituent being an amino group, hydroxyl group, carboxyl group, (C1-C4 alkoxy)carbonyl group, a group having the formula xe2x80x94NHxe2x80x94A1a (wherein, A1a represents a glycyl, alanyl, xcex2-aspartyl or xcex3-glutamyl group) or a group having the formula xe2x80x94COxe2x80x94A2a (wherein, A2a represents a glycino, alanino, valino, leucino, phenylglycino or phenylalanino group)], a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group,
R5 and R6 are the same or different and each independently represents a hydrogen atom, C1-C4 alkyl group, carboxyl group, (C1-C4 alkoxy)carbonyl group, carbamoyl group, (C1-C4 alkyl)carbamoyl group or di-(C1-C4 alkyl)carbamoyl group, and
X represents a sulfur atom, sulfinyl group or sulfonyl group,
(12) compounds wherein R3 represents a 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-azetidinyl, 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-pyrrolidinyl, 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-piperidinyl or 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-3-(xe2x95x90CR5R6)-1-piperidinyl group,
R4 represents a substituted or unsubstituted phenyl group (the substituent being a fluorine atom, chlorine atom, bromine atom, methyl group, methoxy group, nitro group or cyano group), a substituted or unsubstituted straight C1-C4 alkyl group [the substituent being an amino group, hydroxyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, a group having the formula xe2x80x94NHxe2x80x94A1b (wherein, A1b represents a glycyl or xcex3-glutamyl group) or a group having the formula xe2x80x94COxe2x80x94A2b (wherein, A2b represents a glycino, alanino or valino group)], a cyclopentyl group or a cyclohexyl group,
R5 and R6 are the same or different and each independently represents a hydrogen atom, methyl group, ethyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, N,N-dimethylcarbamoyl group or N,N-diethylcarbamoyl group, and
X represents a sulfur atom, the sulfinyl group or sulfonyl group,
(13) compounds wherein R3 represents a 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-azetidinyl, 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-pyrrolidinyl, 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-piperidinyl or 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-3-(xe2x95x90CR5R6)-1-piperidinyl group,
R4 represents a substituted or unsubstituted phenyl group (the substituent being a fluorine atom, chlorine atom, methyl group, methoxy group or nitro group), a substituted or unsubstituted methyl, ethyl or propyl group [the substituent being an amino group, hydroxyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, a group having the formula xe2x80x94NHxe2x80x94A1c (wherein, A1c represents a xcex3-glutamyl group) or a group having the formula xe2x80x94COxe2x80x94A2c (wherein, A2c represents a glycino group)], a cyclopentyl group or a cyclohexyl group,
R5 represents a hydrogen atom,
R6 represents a hydrogen atom, methyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, methylcarbamoyl or N,N-dimethylcarbamoyl group, and
X represents a sulfur atom, sulfinyl or sulfonyl group, and
(14) compounds wherein R3 represents a 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-azetidinyl, 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-pyrrolidinyl, 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-piperidinyl or 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-3-(xe2x95x90CR5R6)-1-piperidinyl group,
R4 represents a substituted or unsubstituted phenyl group (the substituent being a fluorine atom, chlorine atom, methyl group, methoxy group or nitro group), a substituted or unsubstituted methyl, ethyl or propyl group [the substituent being an amino group, hydroxyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, a group having the formula xe2x80x94NHxe2x80x94A1c (wherein, A1c represents a xcex3-glutamyl group) or a group having the formula xe2x80x94COxe2x80x94A2c (wherein, A2c represents a glycino group)], a cyclopentyl group or a cyclohexyl group,
R5 represents a hydrogen atom,
R6 represents a carboxyl, methoxycarbonyl or ethoxycarbonyl group, and
X represents a sulfur atom or sulfonyl group.
Concerning R1, preference for the above-described compounds increases in the order of (1) to (3) and (4) to (6), concerning R2, preference for the compounds increases in the order of (7) to (10) and concerning R3, preference for the compounds increases in the order of (11) to (14).
Examples of the cyclic amino group represented by the formula (I) or pharmacologically acceptable salt thereof, or medicament containing the same include any combination of 2 to 4 substituent definitions selected from the groups consisting of (1) to (3), (4) to (6), (7) to (10) and (11) to (14). The following compounds are preferred combinations:
(15) compounds wherein R1 represents a substituted phenyl group (the substituent being a halogen atom, methyl group, ethyl group, difluoromethyl group, trifluoromethyl group, methoxy group, ethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group or nitro group),
the number of substituents for the substituted phenyl group as R1 ranges from 1 to 3,
R2 represents a substituted or unsubstituted C2-C4 alkanoyl or (C3-C6 cycloalkyl)carbonyl group (the substituent being a fluorine atom, chlorine atom, methoxy group, ethoxy group or cyano group), a substituted or unsubstituted benzoyl group (the substituent being a fluorine atom, chlorine atom, methyl group, ethyl group, methoxy group or ethoxy group), or a (C1-C4 alkoxy)carbonyl group,
(16) compounds wherein R1 represents a substituted phenyl group (the substituent being a fluorine atom, chlorine atom, bromine atom, trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group or nitro group),
the number of substituents for the substituted phenyl group as R1 is 1 or 2,
R2 represents a substituted or unsubstituted C2-C4 alkanoyl or (C3-C6 cycloalkyl)carbonyl group (the substituent being a fluorine or chlorine atom), a benzoyl group or a (C1-C4 alkoxy)carbonyl group,
(17) compounds wherein R1 represents a substituted phenyl group (the substituent being a fluorine atom, chlorine atom, bromine atom, trifluoromethyl group, difluoromethoxy group, trifluoromethoxy group, cyano group or nitro group),
the position of the substituent for the substituted phenyl group as R1 is the 2- or 4-position,
R2 represents a substituted or unsubstituted C2-C4 alkanoyl or (C3-C6 cycloalkyl)carbonyl group (the substituent being a fluorine or chlorine atom), a benzoyl group or a (C1-C4 alkoxy)carbonyl group,
R3 represents a 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-azetidinyl, 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-pyrrolidinyl, 3- or 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-piperidinyl, 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-3-(xe2x95x90CR5R6)-1-piperidinyl or 8-aza-3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-bicyclo[3.2.1]octan-8-yl group,
R4 represents a substituted or unsubstituted phenyl group (the substituent being a halogen atom, methyl group, ethyl group, methoxy group, ethoxy group, nitro group or cyano group), a substituted or unsubstituted straight C1-C6 alkyl group [the substituent being an amino group, hydroxyl group, carboxyl group, (C1-C4 alkoxy)carbonyl group, a group having the formula xe2x80x94NHxe2x80x94A1a (wherein, A1a represents a glycyl, alanyl, xcex2-aspartyl or xcex3-glutamyl group) or a group having the formula xe2x80x94COxe2x80x94A2a (wherein, A2a represents a glycino, alanino, valino, leucino, phenylglycino or phenylalanino group)], a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group,
R5 and R6 are the same or different and each independently represents a hydrogen atom, C1-C4 alkyl group, carboxyl group, (C1-C4 alkoxy)carbonyl group, carbamoyl group, (C1-C4 alkyl)carbamoyl or di-(C1-C4 alkyl)carbamoyl group, and
X represents a sulfur atom, sulfinyl group or sulfonyl group,
(18) compounds wherein R1 represents a substituted phenyl group (the substituent being a fluorine atom or chlorine atom),
the position of the substituent for the substituted phenyl group as R1 is the 2- or 4-position,
R2 represents a substituted or unsubstituted acetyl, propionyl, isobutyryl, cyclopropylcarbonyl or cyclobutylcarbonyl group (the substituent being a fluorine atom), methoxycarbonyl or ethoxycarbonyl group,
R3 represents a 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-azetidinyl, 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-pyrrolidinyl, 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-piperidinyl or 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-3-(xe2x95x90CR5R6)-1-piperidinyl group,
R4 represents a substituted or unsubstituted phenyl group (the substituent being a fluorine atom, chlorine atom, bromine atom, methyl group, methoxy group, nitro group or cyano group), a substituted or unsubstituted straight C1-C4 alkyl group [the substituent being an amino group, hydroxyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, a group having the formula xe2x80x94NHxe2x80x94A1b (wherein, A1b represents a glycyl or xcex3-glutamyl group) or a group having the formula xe2x80x94COxe2x80x94A2b (wherein, A2b represents a glycino, alanino or valino group)], a cyclopentyl group or a cyclohexyl group,
R5 and R6 are the same or different and each independently represents a hydrogen atom, methyl group, ethyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, N,N-dimethylcarbamoyl group or N,N-diethylcarbamoyl group, and
X represents a sulfur atom, sulfinyl group or sulfonyl group,
(19) compounds wherein R1 represents a substituted phenyl group (the substituent being a fluorine atom or chlorine atom),
the position of the substituent for the substituted phenyl group as R1 is the 2- or 4-position,
R2 represents a propionyl, cyclopropylcarbonyl, methoxycarbonyl or ethoxycarbonyl group,
R3 represents a 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-azetidinyl, 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-pyrrolidinyl, 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-piperidinyl or 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-3-(xe2x95x90CR5R6)-1-piperidinyl group,
R4 represents a substituted or unsubstituted phenyl group (the substituent being a fluorine atom, chlorine atom, methyl group, methoxy group or nitro group), a substituted or unsubstituted methyl, ethyl or propyl group [the substituent being an amino group, hydroxyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, a group having the formula xe2x80x94NHxe2x80x94A1c (wherein, A1c represents a xcex3-glutamyl group) or a group having the formula xe2x80x94COxe2x80x94A2c (wherein, A2c represents a glycino group)], a cyclopentyl group or a cyclohexyl group,
R5 represents a hydrogen atom,
R6 represents a hydrogen atom, methyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, methylcarbamoyl group or N,N-dimethylcarbamoyl group, and
X represents a sulfur atom, sulfinyl group or sulfonyl group, and
(20) compounds wherein R1 represents a substituted phenyl group (the substituent being a fluorine atom or chlorine atom),
the position of the substituent for the substituted phenyl group as R1 is the 2- or 4-position,
R2 represents a propionyl, cyclopropylcarbonyl, methoxycarbonyl or ethoxycarbonyl group,
R3 represents a 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-azetidinyl, 3-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-pyrrolidinyl, 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-1-piperidinyl or 4-(xe2x80x94Sxe2x80x94Xxe2x80x94R4)-3-(xe2x95x90CR5R6)-1-piperidinyl group,
R4 represents a substituted or unsubstituted phenyl group (the substituent being a fluorine atom, chlorine atom, methyl group, methoxy group or nitro group), a substituted or unsubstituted methyl, ethyl or propyl group [the substituent being an amino group, hydroxyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, a group having the formula xe2x80x94NHxe2x80x94A1c (wherein, A1c represents a xcex3-glutamyl group) or group having the formula xe2x80x94COxe2x80x94A2c (wherein, A2c represents a glycino group)], a cyclopentyl group or a cyclohexyl group,
R5 represents a hydrogen atom,
R6 represents a carboxyl, methoxycarbonyl or ethoxychloroyl group, and
X represents a sulfur atom or sulfonyl group.
Preference to the above-described compounds increases in the order of (15) to (20).
As typical compounds of the present invention, the compounds shown in the below-described tables can be mentioned by way of example. It should however be borne in mind that the present invention is not limited to them.
Incidentally, the abbreviations in the tables are as follows:
In the Tables, preferred compounds are exemplified compounds numbers 1-2, 1-6, 1-7, 1-10, 1-12, 1-13, 1-14, 1-16, 1-17, 1-20, 1-22, 1-27, 1-30, 1-32, 1-34, 1-36, 1-37, 1-40, 1-42, 1-47, 1-50, 1-52, 1-54, 1-56, 1-57, 1-60, 1-62, 1-67, 1-70, 1-72, 1-74, 1-76, 1-77, 1-80, 1-81, 1-82, 1-83, 1-84, 1-86, 1-87, 1-89, 1-90, 1-109, 1-110, 1-112, 1-114, 1-122, 1-124, 1-139, 1-140, 1-142, 1-144, 1-145, 1-146, 1-152, 1-154, 1-182, 1-184, 1-189, 1-192, 1-194, 1-199, 1-202, 1-204, 1-206, 1-210, 1-214, 1-216, 1-222, 1-225, 1-230, 1-234, 1-236, 1-238, 1-242, 1-244, 1-250, 1-252, 1-258, 1-260, 1-266, 1-268, 1-274, 1-276, 1-301, 1-305, 1-315, 1-318, 1-354, 1-356, 2-2, 2-7, 2-10, 2-12, 2-14, 2-16, 2-17, 2-20, 2-22, 2-27, 2-30, 2-32, 2-34, 2-36, 2-37, 2-40, 2-42, 2-47, 2-50, 2-52, 2-54, 2-56, 2-57, 2-60, 2-62, 2-67, 2-70, 2-72, 2-74, 2-76, 2-77, 2-80, 2-82, 2-84, 2-86, 2-89, 2-109, 2-112, 2-114, 2-122, 2-124, 2-139, 2-140, 2-142, 2-144, 2-145, 2-152, 2-154, 2-182, 2-192, 2-202, 2-206, 2-210, 2-214, 2-222, 2-230, 2-234, 2-236, 2-238, 3-7, 3-12, 3-17, 3-20, 3-27, 3-32, 3-37, 3-40, 3-47, 3-52, 3-57, 3-60, 3-67, 3-72, 3-77, 3-80, 3-82, 3-84, 3-86, 3-89, 3-109, 3-122, 3-124, 3-139, 3-142, 3-144, 3-145, 3-152, 3-182, 3-192, 3-202, 3-206, 3-210, 3-214, 3-234, 3-236, 3-238, 4-2, 4-4, 4-10, 4-12, 4-18, 4-20, 4-26, 4-28, 4-36, 4-61, 4-65, 4-75, 4-78, 4-114, 4-116, 5-1, 5-2, 5-5, 5-6, 5-9, 5-10, 5-13, 5-14, 5-17, 5-25, 5-35, 5-37, 5-39, 5-41, 5-42, 5-45, 5-46, 5-49, 5-50, 5-53, 5-54, 5-57, 5-65, 5-75, 5-77, 5-79, 5-81, 5-82, 5-85, 5-86, 5-89, 5-90, 5-93, 5-94, 5-97, 5-105, 5-115, 5-117, 5-119, 5-121, 5-125, 5-126, 5-129, 5-133, 5-134, 5-137, 5-141, 5-145, 5-149, 5-150, 5-153, 5-157, 5-158, 5-161, 5-162, 5-169, 5-170, 5-171, 5-172, 5-179, 5-180, 5-181, 5-185, 5-186, 5-189, 5-193 and 5-194.
More preferred compounds are exemplified compounds numbers 1-2, 1-7, 1-10, 1-12, 1-14, 1-16, 1-17, 1-20, 1-22, 1-27, 1-30, 1-32, 1-34, 1-36, 1-37, 1-40, 1-42, 1-47, 1-50, 1-52, 1-54, 1-56, 1-57, 1-60, 1-62, 1-67, 1-70, 1-72, 1-74, 1-76, 1-77, 1-80, 1-81, 1-82, 1-83, 1-84, 1-86, 1-87, 1-89, 1-90, 1-109, 1-110, 1-122, 1-124, 1-139, 1-140, 1-142, 1-144, 1-145, 1-146, 1-182, 1-189, 1-192, 1-199, 1-202, 1-206, 1-210, 1-214, 1-216, 1-234, 2-7, 2-14, 2-17, 2-20, 2-27, 2-32, 2-37, 2-40, 2-47, 2-52, 2-57, 2-60, 2-67, 2-72, 2-77, 2-80, 2-82, 2-84, 2-86, 2-89, 2-109, 2-122, 2-124, 2-142, 2-144, 2-145, 2-202, 2-206, 2-210, 2-214, 2-234, 3-7, 3-12, 3-17, 3-20, 3-27, 3-32, 3-37, 3-40, 3-47, 3-52, 3-57, 3-60, 3-67, 3-72, 3-77, 3-80, 3-82, 3-84, 3-86, 3-89, 3-109, 3-122, 3-124, 3-142, 3-144, 3-145, 3-202, 3-206, 3-210, 3-214, 3-234, 5-1, 5-2, 5-5, 5-9, 5-13, 5-17, 5-37, 5-41, 5-42, 5-45, 5-49, 5-53, 5-57, 5-65, 5-77, 5-81, 5-82, 5-85, 5-89, 5-93, 5-97, 5-117, 5-121, 5-129, 5-137, 5-145, 5-153, 5-161, 5-162, 5-171, 5-172, 5-181 and 5-189.
Still more preferred compounds are exemplified compounds numbers 1-7, 1-10, 1-12, 1-14, 1-17, 1-27, 1-32, 1-34, 1-37, 1-47, 1-52, 1-54, 1-57, 1-67, 1-72, 1-74, 1-77, 1-82, 1-84, 1-86, 1-109, 1-139, 1-142, 1-145, 1-146, 1-189, 1-199, 1-210, 2-7, 2-14, 2-27, 2-32, 2-47, 2-52, 2-67, 2-72, 2-82, 2-142, 3-7, 3-12, 3-27, 3-32, 3-47, 3-52, 3-67, 3-72, 3-82, 3-142, 5-2, 5-5, 5-9, 5-13, 5-17, 5-41, 5-42, 5-45, 5-49, 5-53, 5-57, 5-65, 5-81, 5-82, 5-85, 5-89, 5-93, 5-97, 5-117, 5-129, 5-145, 5-171, 5-172, 5-181 and 5-189.
Of which, the following compounds are particularly preferred:
Exemplified Compound No. 1-7: 1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4-(4-methylphenylsulfonylthio)piperidine,
Exemplified Compound No. 1-10: 1-(2-fluoro-xcex1-methoxycarbonylbenzyl)-4-(4-methylphenylsulfonylthio)piperidine,
Exemplified Compound No. 1-12: 1-(2-chloro-xcex1-methoxycarbonylbenzyl)-4-(4-methylphenylsulfonylthio)piperidine,
Exemplified Compound No. 1-14: 1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4-(4-methylphenylsulfinylthio)piperidine,
Exemplified Compound No. 1-17: 1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4-(4-methylphenyldisulfanil)piperidine,
Exemplified Compound No. 1-27: 4-(4-chlorophenylsulfonylthio)-1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)piperidine,
Exemplified Compound No. 1-47: 1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4-(4-fluorophenylsulfonylthio)piperidine;
Exemplified Compound No. 1-67: 1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4-(4-methoxyphenylsulfonylthio)piperidine,
Exemplified Compound No. 1-82: 1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4-phenylsulfonylthiopiperidine,
Exemplified Compound No. 1-109: 1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4-(2-nitrophenyldisulfanil)piperidine;
Exemplified Compound No. 1-139: 1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4-(2,4-dinitrophenyldisulfanil)piperidine,
Exemplified Compound No. 1-142: 1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4-methylsulfonylthiopiperidine,
Exemplified Compound No. 1-146: 1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4-methylsulfinylthiopiperidine,
Exemplified Compound No. 1-210: 1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-4-(2-methoxycarbonylethyldisulfanil)piperidine,
Exemplified Compound No. 2-7: 1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-3-(4-methylphenylsulfonylthio)pyrrolidine,
Exemplified Compound No. 2-14: 1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-3-(4-methylphenylsulfinylthio)pyrrolidine,
Exemplified Compound No. 3-7: 1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-3-(4-methylphenylsulfonylthio)azetidine,
Exemplified Compound No. 5-2: (E)-1-(2-chloro-xcex1-methoxycarbonylbenzyl)-3-methoxycarbonylmethylidene-4-(4-methylphenylsulfonylthio)piperidine,
Exemplified Compound No. 5-41: (E)-1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)-3-ethoxycarbonylmethylidene-4-(4-methylphenylsulfonylthio)piperidine,
Exemplified Compound No. 5-42: (E)-1-(2-chloro-xcex1-methoxycarbonylbenzyl)-3-ethoxycarbonylmethylidene-4-(4-methylphenylsulfonylthio)piperidine, and
Exemplified Compound No. 5-117: (Z)-4-[(R)-2-amino-2-carboxyethyldisulfanil]-3-carboxymethylidene-1-(xcex1-cyclopropylcarbonyl-2-fluorobenzyl)piperidine
The compounds of the formula (I) according to the present invention are prepared by the process as described below. 
wherein, R1, R2, R3 and R4 have the same meanings as described above.
R3a represents a substituted, 3- to 7-membered, saturated cyclic amino group which may optionally have a fused ring [the essential substituent of said group being a hydroxyl group, while the optional substituent of said group being a group having the formula of xe2x95x90CR5aR6a (wherein, R5a and R6a have the same meanings as R5 and R6, respectively, except a carboxyl group)],
R3b has the same meaning as R3a except that the hydroxyl group is replaced with a halogen atom (preferably, a chlorine or bromine atom), a substituted or unsubstituted C1-C4 alkanesulfonyloxy group (the substituent being a halogen atom, and preferably, a methanesulfonyloxy group) or a substituted or unsubstituted benzenesulfonyloxy group (the substituent being a halogen atom, C1-C4 alkyl group, C1-C4 alkoxy group or nitro group, of which a chlorine atom, methyl group, methoxy group or nitro group is preferred and a p-methyl or p-nitro group is particularly preferred),
R3c has the same meaning as R3a except that the hydroxyl group is replaced with a group having the formula of xe2x80x94Sxe2x80x94COR7 (wherein, R7 represents a C1-C4 alkyl group (with a methyl group being particularly preferred)],
R3d has the same meaning as R3 except for the use of a mercapto group as the essential substituent,
R3e represents a substituted, 3- to 7-membered, saturated cyclic amino group which may optionally have a fused ring [the essential substituent of said group being a group of the formula xe2x80x94Sxe2x80x94SO2xe2x80x94R4 and the optical substituent of said group being a group of the formula xe2x95x90CR5aR6a (wherein, R5a and R6a have the same meanings as described above)], and
M stands for an alkali metal atom (such as lithium, sodium or potassium, of which sodium or potassium are preferred).
Process A is for the preparation of each of the compounds (I).
Step A1 is for the preparation of a compound represented by the formula (III) which step is accomplished by reacting a compound represented by the formula (II) with a halogenating agent or sulfonylating agent.
Examples of the halogenating agent usable here include thionyl halides such as thionyl chloride and thionyl bromide, phosphorus trihalides such as phosphorus trichloride and phosphorus tribromide, phosphorous pentahalides such as phosphorus pentachloride and phosphorus pentabromide, phosphorus oxyhalides such as phosphorus oxychloride and phosphorus oxybromide, and tri(phenyl which may be substituted with a C1-C4 alkyl)phosphine-carbon tetrahalides such as triphenylphosphine-carbon tetrachloride, tritolylphosphine-carbon tetrachloride and triphenylphosphine-carbon tetrabromide, of which thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, triphenylphosphine-carbon tetrachloride, tritolylphosphine-carbon tetrachloride and triphenylphosphine-carbon tetrabromide are preferred; and thionyl chloride, triphenylphosphine-carbon tetrachloride and triphenylphosphine-carbon tetrabromide are particularly preferred.
Examples of the sulfonylating agent usable here include substituted or unsubstituted C1-C4 alkanesulfonyl halides (the substituent being a halogen atom), substituted or unsubstituted C1-C4 alkanesulfonic anhdyrides (the substituents being a halogen atom) and benzenesulfonyl halides which may be substituted, of which the substituted or unsubstituted C1-C4 alkanesulfonyl chlorides (the substituent being a fluorine atom), substituted or unsubstituted C1-C4 alkanesulfonyl bromides (the substituent being a fluorine atom), substituted or unsubstituted C1-C4 alkanesulfonic anhydrides (the substituent being a fluorine atom), benzenesulfonyl chloride which may be substituted and benzenesulfonyl bromide which may be substituted are preferred; the C1-C2 alkanesulfonyl chlorides, trifluoromethanesulfonyl chloride, C1-C2 alkanesulfonic anhydrides, trifluoromethanesulfonic anhydride, benzenesulfonyl chloride, toluenesulfonyl chloride and nitrobenzenesulfonyl bromide are more preferred; and methanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride are particularly preferred.
The reaction of the compound (II) with the halogenating agent is carried out in the presence or absence (preferably, in the presence) of an inert solvent. There is no particular limitation on the nature of the inert solvent to be employed in the above-described reaction provided that it does not take part in the reaction. Examples include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, nitriles such as acetontrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methyl-2-pyrrolidone and hexamethylphosphoramide, and sulfoxides such as dimethyl sulfoxide; and mixed solvents thereof, of which the ethers and halogenated hydrocarbons are preferred.
Although the reaction temperature depends on the nature of the raw material compound (II), halogenating agent and solvent, it usually ranges from xe2x88x9210xc2x0 C. to 200xc2x0 C. (preferably, from 0 to 100xc2x0 C.). The reaction time ranges from 30 minutes to 24 hours (preferably from 1 to 12 hours), though depending on the reaction temperature and the like.
The compound (II and the sulfonylating agent are reacted in an inert solvent in the presence or absence (preferably in the presence) of a base and an inert solvent similar to those used for the above-described reaction of the compound (II) with the halogenating agent are usable here.
Examples of the base usable in this reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; and organic amines such as triethylamine, tributylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, picoline, lutidine, collidine, 1,5-diazabicyclo[4.3.0]-5-nonene and 1,8-diazabicyclo[5.4.0]-7-undecene, of which the alkali metal carbonates and organic amines are preferred; and sodium carbonate, potassium carbonate, triethylamine, tributylamine, ethyldiisopropylamine, pyridine and lutidine are particularly preferred. When the organic amine is used in the liquid form, it can be used in a large excess for serving also as a solvent.
Although the reaction temperature depends on the nature of the raw material compound (II), sulfonylating agent and solvent, it usually ranges from xe2x88x9210xc2x0 C. to 100xc2x0 C. (preferably, from 0 to 50xc2x0 C.). The reaction time ranges from 30 minutes to 24 hours (preferably from 1 to 10 hours), though depending on the reaction temperature and the like.
After completion of the reaction, the desired compound of each of the reactions is collected from the reaction mixture in a conventional manner, for example, by filtering off insoluble matter, if any, as needed, and distilling off the solvent under reduced pressure; or by distilling off the solvent under reduced pressure, adding water to the residue, extracting the mixture with a water immiscible organic solvent such as ethyl acetate, drying over anhydrous magnesium sulfate and distilling off the solvent. If necessary, the residue can be purified further in a conventional manner such as recrystallization or column chromatography.
Step A2 is a step for preparing a compound of the formula (V), which step is accomplished by reacting the compound (III) with a compound of the formula (IV) in an inert solvent.
There is no particular limitation on the nature of the inert solvent to be employed in the above-described reaction provided that it does not adversely affect the reaction. Examples include ethers such as diethyl ether, tetrahydrofuran and dioxane; ketones such as acetones and methyl ethyl ketone, esters such as ethyl acetate and butyl acetate, alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol and butyl alcohol; nitriles such as acetonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N -methyl-2-pyrrolidone and hexamethylphosphoramide; and sulfoxides such as dimethyl sulfoxide; and mixed solvents thereof. Preferred are the alcohols, amides and sulfoxides.
Although the reaction temperature depends on the nature of the raw material compound (III), raw material compound (IV) and solvent, it usually ranges from 0 to 200xc2x0 C. (preferably from 20 to 150xc2x0 C.). The reaction time ranges from 30 minutes to 24 hours (preferably, from 1 to 12 hours), though depending on the reaction temperature and the like.
After completion of the reaction, the desired compound of this reaction is collected from the reaction mixture in a conventional manner, for example, by filtering off insoluble matter, if any, as needed and then distilling off the solvent under reduced pressure; or by distilling off the solvent under reduced pressure, adding water to the residue, extracting the mixture with a water immiscible organic solvent such as ethylene acetate, drying over anhydrous magnesium sulfate and distilling off the solvent. If necessary, the residue can be purified further in a conventional manner such as recrystallization or column chromatography.
Step A3 is a step for the preparation of a compound represented by the formula (IV), which step comprises:
Reaction (a) for converting the group which is contained in R3c and has the formula xe2x80x94Sxe2x80x94COR7 (wherein, R7 has the same meaning as described above) into a mercapto group, and if necessary,
Reaction (b) for converting the alkoxycarbonyl group contained in R3c into a carboxyl group or another alkoxycarbonyl group, and
Reaction (c) for isomerizing the cis/trans form based on the double bond contained in R3c. These reactions are conducted in the order changed as needed.
Reaction (a):
The conversion of the group having the formula of xe2x80x94Sxe2x80x94COR7 (wherein R7 has the same meaning as described above) into a mercapto group in this Reaction (a) is attained by subjecting the corresponding compound to hydrolysis or alcoholysis by using an acid or alkali (preferably, the acid). It is carried out in a manner well known in organic synthetic chemistry.
Reaction (a) and Reaction (b) which will be described later can be conducted simultaneously by selecting the reaction conditions (temperature, nature of the acid or alkali, using amount thereof, solvent, and the like) for this hydrolysis as needed.
Examples of the acid usable for this reaction include inorganic acids such as hydrogen chloride, nitric acid, hydrochloric acid and sulfuric acid and organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid, of which hydrogen chloride, hydrochloride acid, sulfuric acid and trifluoroacetic acid are preferred, and hydrogen chloride and hydrochloric acid are particularly preferred.
Examples of the alkali usable for this reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate and alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, of which the alkali metal hydroxides (particularly, sodium hydroxide) are preferred.
There is not particular limitation on the nature of the inert solvent to be employed in the above-described reaction provided that it does not adversely affect the reaction. Examples include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol and butyl alcohol, carboxylic acids such as formic acid, acetic acid, propionic acid and butanoic acid, and water; and mixed solvents thereof. For hydrolysis with the acid, the alcohols, carboxylic acids and water and mixed solvents thereof are preferred, while for hydrolysis by using the alkali, the alcohols and water are preferred.
Although the reaction temperature differs with the nature of the raw material compound (V), acid, alkali and solvent, it usually ranges from xe2x88x9210 to 70xc2x0 C. (preferably from 0 to 50xc2x0 C.). The reaction time ranges from 30 minutes to 20 days (preferably from 1 hour to 12 days), though depending on the reaction temperature and the like.
After completion of the reaction, the desired compound of the reaction is collected from the reaction mixture in a conventional manner, for example, by filtering off insoluble matter, if any, as needed, neutralizing the reaction mixture as needed if it is acidic or alkaline, and distilling off the solvent under reduced pressure; or by distilling off the solvent under reduced pressure, adding water to the residue; extracting the mixture with a water immiscible organic solvent such as ethyl acetate, drying over anhydrous magnesium sulfate and then distilling off the solvent. If necessary, the residue can be purified further in a conventional manner such as recrystallization or column chromatography.
Reaction (b):
Reaction (b) for converting the alkoxycarbonyl group contained in R3c into a carboxyl group is conducted in a similar manner to Reaction (a) for converting the group having the formula of xe2x80x94Sxe2x80x94COR7 (wherein, R7 has the same meaning as described above) into a mercapto group. When R3c and R2 both contain an alkoxycarbonyl group, the alkoxycarbonyl group contained in R3c can selectively be converted into a carboxyl group after being distinguished from that contained in R2 by properly selecting hydrolysis conditions or by using a compound different in the alkoxy part between R2 and R3c (for example, by using a compound containing as R2 a methoxycarbonyl or ethoxycarbonyl group and containing, as the alkoxycarbonyl group contained in R3c, a t-butoxycarbonyl group) and conducting this reaction under acidic conditions.
The conversion of the alkoxycarbonyl group contained in R3c into another alkoxycarbonyl group is conducted easily by reacting it under the conditions similar to the above-described ones (preferably, acidic conditions, more preferably, in the presence of hydrogen chloride) in a solvent of a desired alcohol.
In general, Reaction (b) requires more severe conditions than Reaction (a) so that Reaction (a) and Reaction (b) can be conducted simultaneously by reacting the compound (V) under the conditions of Reaction (b).
After completion of the reaction, the desired compounds of this reaction are collected respectively from the reaction mixture in a conventional manner. In the reaction to convert the alkoxycarbonyl group into a carboxyl group, the desired compound is obtainable by collecting it through filtration as needed when it can be precipitated or it can be precipitated by distilling off the solvent under reduced pressure; or by distilling off the solvent under reduced pressure, adding an acid to adjust the pH of the solution to acidic, extracting with a water immiscible organic solvent such as ethyl acetate, drying over anhydrous magnesium sulfate and then distilling off the solvent. If necessary, the residue can be purified further in a conventional manner such as recrystallization or column chromatography. In the reaction to convert the alkoxycarbonyl group into another alkoxycarbonyl group, on the other hand, the desired compound is obtainable by removing insoluble matter, if any, as needed, neutralizing the reaction mixture as needed if the reaction mixture is acidic or alkaline and distilling off the solvent under reduced pressure; or by distilling off the solvent under reduced pressure, adding water to the residue, extracting the resulting mixture from a water immiscible organic solvent such as ethyl acetate, drying over anhydrous magnesium sulfate and then distilling off the solvent. If necessary, the residue can be purified further in a conventional manner such as recrystallization or column chromatography.
Reaction (c):
Reaction (c) for isomerizing the cis/trans form based on the double bond contained in R3c is conducted by exposing the corresponding compound to light in an inert solvent in the presence or absence (preferably, in the absence) of a sensitizer.
A light source for exposure is a low-pressure mercury lamp (from 20 W to 100 W, preferably 32 W) and examples of the sensitizer include benzophenone, fluorenone and anthraquinone.
The present reaction can be conducted by adding an organic sulfur compound such as dimethyl disulfide, diethyl disulfide or diphenyl disulfide for the purpose of accelerating the reaction and/or suppressing side reactions.
There is no particular limitation on the nature of the inert solvent to be employed in the above-described reaction provided that it does not adversely affect the reaction. Examples include ethers such as diethyl ether, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol and butyl alcohol, nitriles such as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphoramide, sulfoxides such as dimethyl sulfoxide and water; and mixed solvents thereof. Preferred are water, alcohols and nitriles, and mixed solvents thereof.
Although the reaction temperature depends on the nature of the raw material compound, light source and solvent, it usually ranges from xe2x88x9220 to 100xc2x0 C. (preferably 0 to 50xc2x0 C.). The reaction time ranges from 5 minutes to 8 hours (preferably, from 10 minutes to 3 hours), although depending on the reaction temperature and the like.
After completion of the reaction, the desired compound of the present reaction is collected from the reaction mixture in a conventional manner, for example, by removing insoluble matter, if any, by filtration as needed and distilling off the solvent under reduced pressure; or by distilling off the solvent under reduced pressure, adding water to the residue, extracting the mixture from a water immiscible organic solvent such as ethyl acetate, drying over anhydrous magnesium sulfate and then distilling off the solvent. If necessary, the residue can be purified further in a conventional manner such as recrystallization or column chromatography.
Step A4 is a step for preparing the desired compound having the formula (I), which can be roughly classified into:
Reaction (d): for sulfonylating the mercapto group contained in R3d to obtain a sulfonylthio group,
Reaction (e): for sulfinylating the mercapto group contained in R3d to obtain a sulfinylthio group, and
Reaction (f): for sulfenylating the mercapto group contained in R3d to obtain a disulfanyl group.
Reaction (d):
The sulfonylation in Reaction (d) is conducted by reacting the compound (VI) with a compound having the formula of R4SO2Y [wherein, R4 has the same meaning as described above, and Y represents a halogen atom (preferably, a chlorine or bromine atom)] in an inert solvent in the presence or absence (preferably, in the presence) of a base.
There is no particular limitation on the nature of the inert solvent to be employed in the above-described reaction provided that it does not adversely affect the reaction. Examples include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; ketones such as acetone and methyl ethyl ketone; nitriles such as acetonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphoramide; and sulfoxides such as dimethyl sulfoxide; and mixed solvents thereof. Preferred are the halogenated hydrocarbons, hydrocarbons and ethers.
Examples of the base usable in this reaction include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; and organic amines such as triethylamine, tributylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, picoline, lutidine, collidine, 1,5-diazabicyclo[4.3.0]-5-nonene, and 1,8-diazabicyclo[5.4.0]-7-undecene, of which the alkali metal alkoxides and organic amines are preferred; sodium methoxide, sodium ethoxide, triethylamine, tributylamine, ethyldiisopropylamine, N-methylmorpholine and pyridine are more preferred; and triethylamine, tributylamine and ethyldiisopropylamine are particularly preferred.
The compound R4SO2Y is usually added in a molar amount 1 to 15 times, preferably, in a molar amount 1 to 10 times, relative to the compound (VI).
Although the reaction temperature differs with the nature of the compound R4SO2Y and the like, it usually ranges from xe2x88x9210 to 100xc2x0 C. (preferably from 0 to 50xc2x0 C.). The reaction time ranges from 30 minutes to 24 hours (preferably, from 1 to 12 hours), though depending on the reaction temperature and the like.
After completion of the reaction, the desired compound of this reaction is collected from the reaction mixture in a conventional manner, for example, by removing insoluble matter, if any, by filtration as needed, and distilling off the solvent under reduced pressure; or by distilling off the solvent under reduced pressure, adding water to the residue, extracting the mixture with a water immiscible organic solvent such as ethyl acetate, drying over anhydrous magnesium sulfate and then distilling off the solvent. If necessary, the residue can be purified further in a conventional manner such as recrystallization or column chromatography.
Reaction (e):
The sulfinylation in Reaction (e) is conducted by reacting the compound (VI) with a compound having the formula of R4SO2H [wherein, R4 has the same meaning as described above] or an alkali metal salt thereof in an inert solvent in the presence of a condensing agent, or by reacting the compound (VI) with a compound having the formula of R4SOY [wherein, R4 and Y have the same meanings as described above] in an inert solvent in the presence of a base.
The reaction between the compound (VI) with the compound R4SO2H is usually conducted using the compound R4SO2H in an molar amount 1 to 5 times (preferably, in a molar amount 1 to 3 times) relative to the raw material compound (VI). As the condensing agent, dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide is preferably employed and it is used in an equimolar amount relative to the compound R4SO2H.
There is no particular limitation on the nature of the inert solvent to be employed in the above-described reaction provided that it does not adversely affect the reaction. Examples include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethoxyethane; nitriles such as acetonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphopshoramide; and sulfoxides such as dimethyl sulfoxide; and mixed solvents thereof. Preferred are the halogenated hydrocarbons, ethers and amides.
The reaction temperature usually ranges from xe2x88x9210 to 100xc2x0 C. (preferably from 0 to 50xc2x0 C.). The reaction time ranges from 30 minutes to 24 hours (preferably, from 1 to 12 hours), although depending on the reaction temperature and the like.
The reaction between the compound (VI) and the compound R4SOY is conducted under similar reaction conditions to those of Reaction (d) except for the use of the compound R4SOY instead of the compound R4SO2Y.
After completion of the reaction, the desired compound of each of the reactions is collected from the reaction mixture in a conventional manner, for example, by removing insoluble matter, if any, by filtration as needed and distilling off the solvent under reduced pressure; or by distilling off the solvent under reduced pressure, adding water to the residue; extracting the mixture with a water immiscible organic solvent such as ethyl acetate, drying over anhydrous magnesium sulfate and then distilling off the solvent. If necessary, the residue can be purified further in a conventional manner such as recrystallization or column chromatography.
Reaction (f):
The sulfenylation in Reaction (f) is conducted selecting as needed from a process of reacting the compound (VI) with a compound having the formula of R4SYa [wherein, R4 has the same meaning as described above, Ya represents a halogen atom (preferably, a chlorine or bromine atom), alkylsulfonyl group (preferably, a methylsulfonyl group), substituted or unsubstituted phenylsulfonyl group (preferably, a phenylsulfonyl or 4-methylphenylsulfonyl group) or a nitro-substituted phenylthio group (preferably, a 2,4-dinitrophenylthio, 4-nitrophenylthio or 2-nitrophenylthio group)] in an inert solvent in the presence of a base; and a process of reacting the compound (VI) with a compound having the formula of R4SH [wherein, R4 has the same meaning as described above] in an inert solvent in the presence of an oxidizing agent.
The reaction between the compound (VI) and the compound R4SYa can be conducted under similar conditions to those of Reaction (d) except for the use of the compound R4SYa instead of the compound R4SO2Y. When Ya represents a nitro-substituted phenylthio group, the sulfenylation can easily be carried out by converting the compound (VI) into a silver salt thereof and then reacting the salt with the compound R4SYa. The reaction conditions are selected as needed, for example, in accordance with the process as described in Chem. Lett., 813(1975).
The reaction between the compound (VI) and the compound R4SH in the presence of an oxidizing agent is usually conducted using an excess (preferably, in a molar amount 5 to 20 times) of the compound R4SH.
Preferred examples of the oxidizing agent include iodine, bromine, hypochlorous acid, hypobromous acid and hydrogen peroxide, of which iodine is most preferred. The oxidizing agent is usually added in a molar amount 2 to 10 times (preferably, 5 to 10 times) relative to the compound (VI).
There is no particular limitation on the nature of the inert solvent to be employed in the above-described reaction provided that it does not adversely affect the reaction. Examples include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethoxyethane; alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol and butyl alcohol; nitriles such as acetontrile; amides such as N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphoramide; sulfoxides such as dimethyl sulfoxide and water; and mixed solvents thereof. Preferred are the halogenated hydrocarbons, ethers, alcohols and water, and mixed solvents thereof.
The reaction temperature usually ranges from xe2x88x9210 to 100xc2x0 C. (preferably from 0 to 50xc2x00 C.). The reaction time ranges from 30 minutes to 24 hours (preferably, from 1 to 12 hours), though depending on the reaction temperature and the like.
The present reaction may be conducted in the presence of a base in order to suppress side reactions. Examples of such a base include alkali metal carbonates (preferably, sodium carbonate or potassium carbonate) and organic amines (preferably, triethylamine, tributylamine and ethyldiisopropylamine).
After completion of the reaction, the desired compound of the present reaction is collected from the reaction mixture in conventional manner, for example, by removing insoluble matter, if any, by filtration as needed and distilling off the solvent under reduced pressure; or by distilling off the solvent under reduced pressure, adding water to the residue; extracting the mixture with a water immiscible organic solvent such as ethyl acetate, drying over anhydrous magnesium sulfate and then distilling off the solvent. If necessary, the residue can be purified further in a conventional manner such as recrystallization or column chromatography.
Step A5 is another method for preparing a compound having the formula (Ia), that is, a compound (I) having a sulfonyl group as X and it is accomplished by reacting the compound (III) obtainable by Step A2 with a compound represented by the formula (XVII) in an inert solvent in the presence or absence (preferably, in the presence) of a base. The above-described reaction is conducted under similar conditions to Step A2 except for the use of the compound (XVII) instead of the compound (IV).
The compounds (I) may have optical isomers or geometric isomers. In such a case, the desired optical isomer or geometric isomer of the desired compound can be obtained using a raw material compound subjected to optical resolution or separation of a geometric isomer.
It is also possible to treat the optical isomer or geometric isomer mixture in accordance with a conventional optical resolution or separation method in the desired stage of the preparation process, thereby obtaining the corresponding isomer.
The compounds (I) can be converted into a pharmacologically acceptable salt thereof by treating them with an acid in a conventional manner, for example, by reacting them with a corresponding acid in an inert solvent (preferably, ethers such as diethyl ether, tetrahydrofuran or dioxane, alcohols such as methanol or ethanol or halogenated hydrocarbons such as methylene chloride or chloroform) at room temperature for 5 minutes to 1 hour and then distilling off the solvent under reduced pressure.
The raw material compound (II) of the present invention is easily prepared by the following process: 
In the above-described formulae, R1, R2, R3a, R5a and R6a have the same meanings as described above, R8 represents an amino-protecting group which is removed under acidic conditions, R9 represents an amino-protecting group which is removed under reducing conditions, Yb represents a halogen atom (preferably, a chlorine or bromine atom), m stands for 0 to 3 and n stands for 1 or 2.
The amino-protecting group, as R8, removed under acidic conditions is, for example, a trityl group or t-butoxycarbonyl group, while the amino-protecting group, as R9, removed under reducing condition is, for example, a substituted or unsubstituted benzyl or benzyloxycarbonyl group similar to the above-described hydroxyl-protecting groups and preferred examples include benzyl, p-methoxybenzyl, p-chlorobenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl and p-chlorobenzyloxycarbonyl groups, of which the benzyl and p-methoxybenzyl groups are particularly preferred.
Process B is a process for preparing the compound (II).
Step B1 is a step for preparing the compound (II) by reacting a compound having the formula (VII) with a compound having the formula (VIII) in an inert solvent (preferably, an amide such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone or hexamethylphosphoramide or sulfoxide such as dimethyl sulfoxide) in the presence or absence of a base (preferably, in the presence of an alkali metal carbonate such as sodium carbonate or potassium carbonate) at 0 to 200xc2x0 C. (preferably, at 20 to 150xc2x0 C. for 1 to 24 hours (preferably, for 2 to 15 hours).
The compound (II) containing an alkoxycarbonyl group in R3a is hydrolyzed similar to Reaction (b) of Step A3 of Process A to prepare the corresponding carboxylic acid derivative. The resulting carboxylic acid derivative is then reacted with a C1-C4 alkyl halogencarbonate such as methyl chlorocarbonate, ethyl chlorocarbonate, ethyl bromocarbonate, propyl chlorocarbonate, butyl chlorocarbonate or isobutyl chlorocarbonate in the presence of a base such as triethylamine or ethyldiisopropylamine, whereby the corresponding active ester derivative is prepared. The resulting ester derivative is then reacted with ammonia or a mono- or di-(C1-C4 alkyl)amine in an inert solvent (preferably, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane) at xe2x88x9210 to 100xc2x0 C. (preferably, at 10 to 50xc2x0 C.) for 1 to 24 hours (preferably, for 2 to 10 hours), whereby the corresponding amide derivative can be prepared.
After completion of reaction, the desired compound of the present reaction is collected from the reaction mixture in a conventional manner, for example, by removing insoluble matter, if any, by filtration as needed, neutralizing the reaction mixture as needed if it is acidic or alkaline, and distilling off the solvent under reduced pressure; or by distilling off the solvent under reduced pressure, adding water to the residue, extracting the mixture with a water immiscible organic solvent such as ethyl acetate, drying over anhydrous magnesium sulfate and then distilling off the solvent. If necessary, the residue can be purified further in a conventional manner such as recrystallization or column chromatography.
Process C is a process for preparing a compound (VIIa) which is one of the raw material compounds (VII) in Process B and contains a substituent having the formula xe2x95x90CR5aR6a (wherein, R5a and R6a have the same meanings as described above).
Step C1 is a step for preparing a compound represented by the formula (X) and is conducted by reacting a compound having the formula (IX) with a trityl halide such as trityl chloride or trityl bromide, a t-butoxycarbonyl halide such as t-butoxcarbonyl chloride or t-butoxycarbonyl bromide, or di-t-butyl dicarbonate in an inert solvent (preferably, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane, amide such as N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone or hexamethylphosphoramide, or a sulfoxide such as dimethyl sulfoxide) in the presence or absence of a base (preferably, in the presence of an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate or an organic amine such as triethylamine or ethyldiisopropylamine) at 0 to 150xc2x0 C. (preferably, at 20 to 100xc2x0 C. for 1 to 24 hours (preferably, for 2 to 10 hours).
Step C2 is a step for preparing a compound represented by the formula (XII) and is conducted by reacting the compound (X) with a di-(C1-C4 alkyl)amine or a 3- to 6-membered cyclic amine (preferably, dimethylamine, diethylamine, pyrrolidine, piperidine or morpholine, with pyrrolidine, piperidine or morpholine being particularly preferred) in an inert solvent (preferably, an aromatic hydrocarbon such as benzene, toluene or xylene) at 60 to 200xc2x0 C. (preferably, at 80 to 150xc2x0 C.) for 30 minutes to 15 hours (preferably, for 1 to 10 hours) under azeotropic dehydration to prepare the corresponding enamine derivative and then reacting the enamine derivative with a compound having the formula (XI) in an inert solvent (preferably, an aromatic hydrocarbon such as benzene, toluene or xylene) at 60 to 200xc2x0 C. (preferably, at 80 to 150xc2x0 C.) for 30 minutes to 10 hours (preferably, for 1 to 5 hours) under azeotropic dehydration.
Step C3 is a step for preparing a compound represented by the formula (XIII) and is conducted by reacting the compound (XII) with a reducing agent (preferably, a borohydride compound such as sodium borohydride or sodium cyanoborohydride) in an inert solvent (preferably, an alcohol such as methanol or ethanol) at 0 to 100xc2x0 C. (preferably, at 5 to 50xc2x0 C.) for 10 minutes to 6 hours (preferably, for 30 minutes to 3 hours).
Step C4 is a step for preparing the compound (VIIa) which is accomplished by removing amino-protecting group from the compound (XIII). This step is carried out in accordance with the process described in xe2x80x9cProtective Groups in Organic Synthesis, 2nd edition, 309, T. W. Greene and P. G. M. Wuts; John Wiley and Sons, Inc.xe2x80x9d in which process an acid (preferably, p-toluenesulfonic acid or trifluoroacetic acid) is employed.
After completion of the each reaction, the desired compound of this reaction is collected from the reaction mixture in a conventional manner, for example, by removing insoluble matter, if any, by filtration as needed, neutralizing the reaction mixture as needed if it is acidic or alkaline, and distilling off the solvent under reduced pressure; or by distilling off the solvent under reduced pressure, adding water to the residue, extracting the mixture with a water immiscible organic solvent such as ethyl acetate, drying over anhydrous magnesium sulfate and then distilling off the solvent. If necessary, the residue can be purified further in a conventional manner such as recrystallization or column chromatography.
Process D is another method for preparing the intermediate (XII) employed in Process C.
Step D1 is a step for preparing a compound represented by the formula (Xa) and is conducted by reacting the compound (IX) with a substituted or unsubstituted benzyl halide or a substituted or unsubstituted benzyloxycarbonyl halide (preferably, the chloride) in a manner similar to Step C1 of Process C.
Step D2 is a step for preparing a compound represented by the formula (XIV) and is conducted by reacting the compound (Xa) with a di(C1-C4 alkyl)amine or a 3- to 6-membered cyclic amine (preferably, dimethylamine, diethylamine, pyrrolidone, piperidine or morpholine, with pyrrolidine, piperidine or morpholine being particularly preferred) in a similar manner to the first stage of Step C2 of Process C to prepare the corresonding enamine derivative and then reacting the resulting enamine derivative with a compound represented by the formula (XI) in an inert solvent (preferably, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane) in the presence of an acid catalyst (preferably, a Lewis acid such as boron trifluoridexe2x80x94ether complex, aluminum chloride, titanium tetrachloride or tin tetrachloride) at xe2x88x9210 to 100xc2x0 C. (preferably, at 10 to 50xc2x0 C.) for 1 to 24 hours (preferably, for 2 to 20 hours).
Step D3 is a step for preparing a compound represented by the formula (XV) and it is accomplished by removing the amino-protecting group from the compound (XIV). This step is conducted in accordance with the reduction method with hydrogen as described in the above-described xe2x80x9cProtective Groups in Organic Synthesis, 2nd editionxe2x80x9d.
Step D4 is a step for preparing a compound represented by the formula (XVI) and is accomplished by protecting the amino group of the compound (XV). This step is conducted in a similar manner to Step C1 of Process C.
Step D5 is a step for preparing the compound (XII) which comprises sulfonylating the compound (XVI) as in Step A1 of Process A and then reacting the resulting sulfonyloxy derivative with a base (preferably, an organic amine such as triethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]-5-nonene or 1,8-diazabicyclo[5.4.0]-7-undecene) in an inert solvent (preferably, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane) at xe2x88x9210 to 100xc2x0 C. (preferably, at 10 to 50xc2x0 C.) for 30 minutes to 10 hours (preferably, for 1 to 5 hours).
After completion of the reaction, the desired compound of the present reaction is collected from the reaction mixture in a conventional manner, for example, by removing an insoluble matter, if any, by filtration as needed, neutralizing the reaction mixture as needed if it is acidic or alkaline, and distilling off the solvent under reduced pressure; or by distilling off the solvent under reduced pressure, adding water to the residue, extracting the mixture with a water immiscible organic solvent such as ethyl acetate, drying over anhydrous magnesium sulfate and then distilling off the solvent. If necessary, the residue can be purified further in a conventional manner such as recrystallization or column chromatography.
The raw material compound (VIII) is known or prepared in a known manner [e.g. Japanese Patent Application Kokai No. Sho 59-27895 (EP99802), Japanese Patent Application kokai No. Hei 6-41139 (EP542411), or the like]. The raw material compound (VII) is known or prepared in a known manner [e.g. The Journal of Organic Chemistry: J. Org. Chem., 37, 3953(1972)].
The present invention will hereinafter be described in further detail by Examples, Referential Examples, Tests and Formulation Examples. It should however be borne in mind that the scope of the present invention is not limited to or by them.